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Baseline Blood CD8+ T Cell Activation Potency Discriminates Responders from Non-Responders to Immune Checkpoint Inhibition Combined with Stereotactic Radiotherapy in Non-Small-Cell Lung Cancer
by
, , , , , ,
Hanneke Kievit
1,
M. Benthe Muntinghe-Wagenaar
1,
Wayel H. Abdulahad
2,
Abraham Rutgers
2,
Lucie B. M. Hijmering-Kappelle
1,
Birgitta I. Hiddinga
1,
J. Fred Ubbels
3,
Robin Wijsman
3,
Marcel J. van der Leij
4,
Johan Bijzet
2,
Harry J. M. Groen
1,
Huib A. M. Kerstjens
1,
Anthonie J. van der Wekken
1,
Bart-Jan Kroesen
4 and
T. Jeroen N. Hiltermann
1,* 1
Department of Pulmonology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
2
Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
3
Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
4
Department of Laboratory Medicine, Medical Immunology laboratory, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(14), 2592; https://doi.org/10.3390/cancers16142592 (registering DOI)
Submission received: 21 June 2024
/
Revised: 12 July 2024
/
Accepted: 17 July 2024
/
Published: 19 July 2024
(This article belongs to the Special Issue Novel Biomarkers in Non-small Cell Lung Cancer (NSCLC))
Simple Summary
Cancer may be recognized by the immune system. For patients with non-small-cell lung cancer (NSCLC), immune checkpoint inhibitors (ICI) are a first-line treatment in most patients. However, most of these patients do not respond to ICI, implying that the treatment is ineffective, where it may have relevant side effects. Currently, there is no solid biomarker to predict response to ICI. Thus, there is an urgent need for a new biomarker to predict this response, preferably via minimally invasive techniques. We tested the potency of T cells to be activated ex vivo in the peripheral blood of patients with advanced NSCLC. We found an increased ability to activate CD8+ T cells and produce intracellular IL-2 in peripheral CD8+ T cells in patients that respond to ICI compared to non-responders and healthy controls before the start of ICI. The potency of peripheral T cells to be activated before treatment seems a promising biomarker.
Abstract
Background: Tumor-infiltrating immune cells have been correlated with prognosis for patients treated with immune checkpoint inhibitor (ICI) treatment of various cancers. However, no robust biomarker has been described to predict treatment response yet. We hypothesized that the activation potency of circulating T cells may predict response to ICI treatment. Methods: An exploratory analysis was conducted to investigate the association between the response to immune checkpoint inhibition (ICI) combined with stereotactic radiotherapy (SBRT) and the potency of circulating T cells to be activated. Blood-derived lymphocytes from 14 patients were stimulated ex vivo with, among others, Staphylococcal enterotoxin B (SEB) and compared to healthy controls (HCs). Patients were grouped into responders (>median progression free survival (PFS)) and non-responders (<median PFS). The expression of the T cell activation marker CD69 and intracellular cytokines (IL-2, IFNγ, TNFα) in both CD4+ and CD8+ T cells in response to stimulation was measured using flow cytometry. In addition, serum levels of BAFF, IFNγ, and IL-2 receptor (sIL-2R) were measured by Luminex. Results: At baseline, a higher percentage of activated CD8+ T cells (15.8% vs. 3.5% (p = <0.01)) and IL-2+CD69+CD8+ T cells (8.8% vs. 2.9% (p = 0.02)) was observed in responders compared to non-responders upon ex vivo stimulation with SEB. The concurrently measured serum cytokine levels were not different between responders and non-responders. Conclusion: Baseline blood CD8+ T cell activation potency, measured by intracellular cytokine production after ex vivo stimulation, is a potential biomarker to discriminate responders from non-responders to SBRT combined with ICI.
